Cephalosporin antibiotics having an acyloxymethyl group at the C.sub.3 carbon atom of the cephem nucleus are well recognized in the cephalosporin art, see, for example, U.S. Pat. Nos. 3,270,009; 3,278,531; 3,532,694; 3,705,897; 3,728,342; and 3,795,672. New methods for preparing these cephalosporins continually are being sought. This invention is directed to a process for preparing 3-acyloxymethyl-.DELTA..sup.2 -cephem compounds, which compounds are readily convertible by recognized techniques to the aforementioned 3-acyloxymethyl cephalosporin antibiotics.
Recently, 3-exomethylenecepham esters have been described, for example, in Chauvette et al., J. Org. Chem. 38 2994 (1973); and in U.S. Pat. No. 3,792,995. These compounds have the general formula ##STR2##
The corresponding sulfoxides are starting materials employed in the process of this invention and are readily available from the corresponding 3-exomethylenecepham esters by known methods. For example, a 3-exomethylenecepham acid or ester can be reacted with a peracid, for example, (m-chloroperbenzoic) acid, perbenzoic acid, peracetic acid, and the like, to form the corresponding sulfoxide. The 3-exo double bond of the starting material is inert under these conditions of sulfoxide formation, and, consequently, the sulfoxide is prepared by the selective oxidation of the sulfide.
The sulfoxide ester starting materials alternatively and preferably are prepared by a process described by S. Kukolja in co-pending Applications Ser. Nos. 536,273 and 536,280, both filed Dec. 24, 1974 and both now abandoned. According to these described methods, a penicillanic acid ester sulfoxide is reacted with an N-chloro halogenating agent in a dry, inert organic solvent at a temperature between about 70.degree. C. and about 100.degree. C. to provide an azetidinone sulfinyl chloride. The sulfinyl chloride then is reacted with a Lewis acid Friedel-Crafts type catalyst in a dry, inert, organic solvent to effect cyclization and to provide the 3-exomethylenecepham sulfoxide ester.
As indicated, the 3-exomethylenecepham sulfoxide esters represent the starting materials of the process of this invention, and it has now been discovered that it is possible to convert these sulfoxide esters to their corresponding 3-acyloxymethyl-.DELTA..sup.2 -cephems, which class of compounds is useful as intermediates in the preparation of the aforementioned 3-acyloxymethyl cephalosporins (3-acyloxymethyl-.DELTA..sup.3 -cephem compounds).